PDF(Pubmed)
Abstract：
Computational pharmacogenomics can potentially identify new indications for already approved drugs and pinpoint compounds with similar mechanism-of-action. Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238). In vitro validation of candidate compounds was then performed to assess proteasomal proteolytic activity, accumulation of ubiquitinated proteins, cell viability, and drug-induced expression in A375 melanoma and MCF7 breast cancer cells. Using this approach, we identified six compounds with PI properties ((-)-kinetin-riboside, manumycin-A, puromycin dihydrochloride, resistomycin, tegaserod maleate, and thapsigargin). Although the docking scores pinpointed their ability to bind to the β5 subunit, our in vitro study revealed that these compounds inhibited the β1, β2, and β5 catalytic sites to some extent. As shown with bortezomib, only manumycin-A, puromycin dihydrochloride, and tegaserod maleate resulted in excessive accumulation of ubiquitinated proteins and elevated HMOX1 expression. Taken together, our integrated drug repositioning approach and subsequent in vitro validation studies identified six compounds demonstrating properties similar to proteasome inhibitors.
摘要：
计算药物基因组学可以潜在地确定已经批准的药物的新适应症，并确定具有相似作用机制的化合物。这里,我们使用基于转录组学数据和基于结构的虚拟筛选的综合药物重定位方法来鉴定具有与三种已知蛋白酶体抑制剂（PIs;硼替佐米，MG-132和MLN-2238）。然后进行候选化合物的体外验证以评估蛋白酶体蛋白水解活性，泛素化蛋白质的积累，细胞活力，和药物在A375黑色素瘤和MCF7乳腺癌细胞中的诱导表达。使用这种方法，我们确定了六个具有PI性质的化合物（（-）-激动素-核苷，Manumycin-A,盐酸嘌呤霉素,抗霉素，马来酸替加色罗德,和thapsigargin）。尽管对接评分确定了它们与β5亚基结合的能力，我们的体外研究表明，这些化合物在一定程度上抑制了β1，β2和β5催化位点。如硼替佐米所示，只有Manumycin-A,盐酸嘌呤霉素,和马来酸替加色罗导致泛素化蛋白的过度积累和HMOX1表达升高。一起来看,我们的综合药物重定位方法和随后的体外验证研究鉴定出6种化合物,这些化合物具有与蛋白酶体抑制剂相似的性质.
